Introduction

In the last decade the focus of research into the pathophysiology of critical illness, specifically the sepsis syndrome, has been on the role of inflammatory and anti-inflammatory mediators with cytokines being the major players. The intricate cascade of events in this syndrome is complicated by the dual effect of cytokines and pro- and anticoagulants on both the coagulation system and the inflammatory process. Many of the mediators that are under scrutiny have also been implicated in the derailment of different endocrinological systems during critical illness. However, this interaction is still poorly understood.

Our current understanding of the pathophysiology of the endocrinological derailments as a consequence (not a direct cause) of critical illness, especially secondary to systemic inflammatory response syndrome (SIRS) and sepsis, is primarily based on research performed in human medicine. Based on this knowledge, some (new) therapeutic options will be discussed.

Pancreas

Glucose metabolism in critical illness is characterised primarily by insulin resistance and hyperglycaemia. Both inflammatory mediators (the cytokines interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) and hormones (counter-regulatory hormones, resistin, leptin and adiponectin) independently increase insulin resistance. The interest in controlling hyperglycaemia during critical illness was sparked by the 'Leuven I' study in 2001. This study demonstrated a reduction in morbidity and mortality among critically ill patients in the surgical intensive care unit after tight control of plasma glucose levels with a continuous rate infusion of insulin. However, this result could not be repeated by many studies that followed, some of which even demonstrated an increased risk for the development of hypoglycaemia, especially in patients that are more critically ill. Currently routine intensive insulin therapy cannot be recommended in veterinary intensive care patients as our means to prevent development of hypoglycaemia are even more limited. However, some reports suggest there might exist a similar pathophysiology in companion animals.

Adrenal Glands

The hypothalamic-pituitary-adrenocortical (HPA) axis is activated in critical illness and hypercortisolaemia is an essential part of the stress response required for adequate adaptation. Critical illness-related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterised by an exaggerated and protracted proinflammatory response. Because it is not an absolute deficiency but rather an imbalance between adrenal output and cortisol demand, this disorder is labelled 'critical illness-related corticosteroid insufficiency' (CIRCI). The presence of CIRCI in dogs and cats has also been suggested in the veterinary literature.

Cytokines such as TNF-α and interleukin-1 (IL-1) have been demonstrated to cause reversible dysfunction of the HPA axis and to be involved in the development of resistance to glucocorticoids at the tissue level. Also disseminated intravascular coagulation (DIC) may contribute by adrenal hypoperfusion and microvascular disease.

The value of basal hormone levels and dynamic testing has been limited in testing adrenal function in CIRCI. Furthermore, these tests do not reflect the peripheral resistance that also may exist. Therefore, a more 'practical' approach has been suggested in human medicine; according to current clinical human recommendations CIRCI may be considered if there is the presence of hypotension despite both adequate fluid resuscitation and the use of vasopressors, particularly in the setting of sepsis. This hypotension may be related to the downregulation of smooth muscle adrenergic receptors of which the expression is modulated by glucocorticosteroids. The use of steroids is also recommended in patients with severe acute respiratory distress syndrome during the early phase of the disease. The efficacy of this approach has not yet been demonstrated in dogs and cats.

Routine administration of a physiological dose of steroids to patients should be discouraged as improved outcome in humans is limited to only a specific group of critically ill patients and the use of steroids is associated with complications such as nosocomial infection.

Pituitary Gland

Disorders of sodium and water balance are exceedingly common in hospitalised patients, particularly with critical illness, and are often iatrogenic. Although there are many causes the focus here is on the role of arginine vasopressin (AVP). The syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) is characterised by an inappropriate or persistent release of AVP that results in a decreased capacity for free water excretion. This syndrome is the most common cause of acquired hyponatraemia in hospitalised human patients and causes isovolaemic hypoosmolar hyponatraemia. A reduction in plasma sodium concentration creates an osmotic gradient that favours water movement into the brain. This increase in brain intracellular volume contributes to cerebral oedema and raised intracranial pressure and leads to the appearance of neurological manifestations. Besides the hyponatraemia, a reduction in urine output can be noted and it is sometimes the only symptom that will make us consider the possibility of SIADH in an euvolaemic patient.

Making a diagnosis of SIADH is complicated and in veterinary medicine it often remains only a suspicion following the ruling out of as many other causes of hyponatraemia as possible (hypoadrenocorticism, hypothyroidism, recent diuretic use and hospital-acquired fluid imbalance). The causes of SIADH can be broadly categorised into disorders of the central nervous system, pulmonary disorders, disorders associated with medications or tumours and a variety of miscellaneous causes. Mechanical ventilation and the use of opiates can lead to SIADH in critically ill patients.

Besides its role in SIADH, vasopressin has an influence on a multitude of other hormones, including the HPA axis and may be of significance in critical illness in many other ways.

Thyroid Glands

Critically ill patients show uniform disturbances in the hypothalamus-pituitary-thyroid axis. There is clear evidence that circulating and tissue thyroxine levels are low and this is called the low tri-iodothyronine (T3) syndrome, euthyroid sick syndrome or non-thyroidal illness syndrome. The clinical importance of the low T3 syndrome is still not very clear because it can either protect against or aggravate the catabolic state. Recently, novel insights were generated into the pathophysiology of the low T3 syndrome. Recent studies in animal models as well as in human patients have shown alterations in thyroxine transport and also in deiodinase activity which, together, may suggest an attempt by certain peripheral tissues, as well as by the hypothalamus, to compensate for low circulating thyroxine levels. Currently, the treatment of this syndrome is not advocated.

Conclusion

Currently, many derailments of the endocrinological systems in human critically ill patients are recognised and their role in patient outcome is under investigation. Early recommendations to evaluate abnormalities in the endocrinological system and to address them in the management of patients with sepsis exist, but they remain under close scrutiny. In the veterinary literature there are few reports that indicate similar endocrine derailments but without a clear picture in human literature and with the limited knowledge and research capabilities in veterinary medicine no clear recommendations for treatment in critically ill dogs and cats can be made.

The author would like to acknowledge Dr C. Valtolina DipACVECC for her help in the preparation of these notes.

References

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